(a) Field of Invention
This invention relates to analogs of the tetradecapeptide somatostatin. More particularly, this invention concerns somatostatin analogs in which the tryptophyl residue at position eight is replaced by a tryptophyl residue having a fluoro, bromo, chloro or iodo substituent at position 5 or 6 of the indole ring system and salts thereof, a process for preparing the analogs and salts, intermediates used in the process and methods for using the somatostatin analogs and their salts.
(b) Prior Art
The name "somatostatin" has been proposed for the factor found in hypothalamic extracts which inhibits the secretion of growth hormone (somatotropin). The structure of this factor has been elucidated by P. Brazeau et al., Science, 179, 77(1973) and reported to have the following tetradecapeptide structure: ##STR2##
The constitution of the tetradecapeptide somatostatin has been confirmed by synthesis; for example, see D. Sarantakis and W. A. McKinley, Biochem. Biophys. Res. Comm., 54, 234(1973) and H. U. Immer et al., Helv. Chim. Acta, 57, 730(1974).
The important physiological activity of this tetradecapeptide established it as a compound of significance for clinical pharmacology relating to the treatment of acromegaly and the management of diabetes; for example, see K. Lundbaek et al., Lancet, 2, 131(1970) and A. Gordin et al., Acta Endocrinologica, 86, 833-841(1977).
Since the structure and physiological activity of somatostatin were determined, a number of somatostatin analogs have been reported. One of the more important analogs, [D-Trp].sup.8 -somatostatin, reported by J. Rivier et al., Biochem. Biophys. Res. Commun., 65, 746(1975) and D. H. Coy et al., Endocrinology, 98, 305A(1976), is five to eight times more active than somatostatin on the inhibition of growth hormone release in vitro.
The present invention discloses novel somatostatin analogs in which the tryptophyl residue at position eight is replaced by a tryptophyl residue having a fluoro, bromo, chloro or iodo substituent at position 5 or 6 of the indole ring system. Surprisingly, the somatostatin analogs of the present invention have been found to be more active in inhibiting growth hormone in vitro than the corresponding natural somatostatin or [D-Trp].sup.8 -somatostatin. This result indeed is surprising and unexpected in view of the fact that replacement of a tryptophyl residue with a substituted tryptophyl in other hypothalamic releasing hormones has resulted in a reduction of biological activity. For example, the [5F-Trp].sup.3 -LH-RH analog, is reported by D. H. Coy et al., Biochemistry, 13, 3550(1974). In the latter instance the analog exhibits only six percent of the activity of the natural LH-RH.